Andra H. James

Trends in the Incidence of Venous Thromboembolism during Pregnancy or Postpartum: A 30-Year Population-Based Study

Context The risk for venous thromboembolism during pregnancy and in the postpartum period has not been well defined by previous studies. Contribution Using 30 years of data, these investigators found that the risk for a first episode of venous thromboembolism is 5 times higher in the postpartum period than during pregnancy. The risk for pulmonary embolism is 15 times greater during the postpartum period than during pregnancy. Implications Women at high risk for venous thromboembolism may require special consideration for anticoagulation in the postpartum period. Cautions The ethnicity of the study population was 98% white. The findings may not be generalizable to other ethnic groups. The Editors Knowledge of the relative risk and incidence (absolute risk) of venous thromboembolism among pregnant and postpartum women is important for identifying patients who would benefit from prophylaxis. However, there are few data regarding the relative risk for venous thromboembolism during pregnancy (1), and the reported incidence of venous thromboembolism among pregnant or postpartum women varies widely. Previous studies reported incidence rates ranging from 18 to 95 events per 100000 woman-years during pregnancy and from 199 to greater than 1900 per 100000 woman-years during the postpartum period (2-7). Substantial variation also exists in the reported incidence of venous thromboembolism by trimester and by time after delivery (8-14). Given the markedly worse survival rate after pulmonary embolism compared with that after deep venous thrombosis alone (15), identification of those pregnant or postpartum women at high risk for pulmonary embolism is especially important. However, the incidence by type of venous thromboembolic event during pregnancy and during the postpartum period is uncertain (8, 10, 13, 14, 16-21). The wide variability in reported rates probably reflects differences in study design. For example, published studies identified cases from a variety of sources, including hospital inpatient databases (2, 3, 16, 22), the United Kingdoms National Health Service (4, 23), and hospital discharge and maternity registries (5, 6). Because of diagnostic uncertainty or misclassification, data from these sources possibly underestimated or overestimated the actual incidence rate. Incidence rates derived from hospital inpatient databases potentially missed venous thromboembolism events that occurred after discharge (2, 3, 5, 7, 22), and rates possibly varied when data were reported by selected strata (23) or when only patients referred to tertiary care centers were included (7). Moreover, most studies did not separate incident from recurrent events or include autopsy-discovered events (13, 24, 25). Finally, only a few studies reported trends in pregnancy-associated venous thromboembolism incidence over time (5, 6, 23). Because of these limitations, we performed a population-based study to estimate the relative risk and incidence of venous thromboembolism during pregnancy and the postpartum period within a well-defined geographic area, and we sought to describe trends in incidence over time. We examined the incidence of pregnancy-associated deep venous thrombosis and pulmonary embolism in women living in Olmsted County, Minnesota, between 1966 and 1995. We calculated incidence during pregnancy, incidence during the first 3 postpartum months, and total incidence. Methods Study Setting and Design Using the data resources of the Rochester Epidemiology Project (26), we identified the inception cohort of Olmsted County residents with a first lifetime deep venous thrombosis or pulmonary embolism diagnosed between 1966 and 1995. We included all female residents of Olmsted County who had a venous thromboembolism during pregnancy or the postpartum period; the postpartum period was defined as delivery of a newborn within 3 months before the deep venous thrombosis or pulmonary embolism event date, including delivery of a stillborn infant after the first trimester (27). The institutional review board of the Mayo Clinic approved the study. Definition of Deep Venous Thrombosis and Pulmonary Embolism A diagnosis of deep venous thrombosis was confirmed by venography, computed tomography, magnetic resonance imaging, impedance plethysmography, continuous-wave Doppler ultrasonography (performed in the Mayo Clinic Vascular Laboratory), compression venous duplex ultrasonography, radionuclide venography, radiolabeled fibrinogen leg scan, or pathologic examination of a thrombus removed at surgery or autopsy. A patient was also included when 1) the medical record indicated that a physician diagnosed deep venous thrombosis (or possible deep venous thrombosis); 2) signs and symptoms consistent with deep venous thrombosis were present; and 3) the patient received a course of anticoagulant therapy with heparin, warfarin, or a similar agent or underwent a surgical procedure for treatment of deep venous thrombosis (27). A diagnosis of pulmonary embolism was confirmed by pulmonary angiography, computed tomography, magnetic resonance imaging, a perfusion or ventilation-perfusion lung scan indicating high probability for pulmonary embolism, or pathologic examination of a thrombus removed at surgery or autopsy. A patient was also included when 1) the medical record indicated that a physician made a diagnosis of pulmonary embolism; 2) signs and symptoms consistent with pulmonary embolism were present; and 3) the patient received a course of anticoagulant therapy with heparin, warfarin, or a similar agent or underwent a surgical procedure for treatment of pulmonary embolism, such as placement of an inferior vena cava filter. We did not include patients who received only short-term anticoagulation while awaiting results of diagnostic evaluation for suspected deep venous thrombosis or pulmonary embolism. Statistical Analysis We also used the resources of the Rochester Epidemiology Project to calculate Olmsted County pregnancy rates. We determined the denominator by using Olmsted County census data from 1970, 1980, 1990, and 2000 for the population estimates, with linear interpolation for the years between censuses. Yearly counts of live births, fetal deaths, and neonatal deaths in Olmsted County from 1966 to 1995 were obtained from published documents from the Minnesota Department of Health (Minnesota Health Statistics Annual Summary). Counts were derived from the residence of the mother rather than the place of birth. We were able to obtain maternal ages for live births in Olmsted County but not for fetal or neonatal deaths. We restricted our study to pregnant women who did not have spontaneous or therapeutic abortions, but we did include stillbirths. We calculated age-specific rates of live births by using the number of live births as the numerator; for the denominator, we used age-specific census estimates of the female population of Olmsted County to estimate person-years at risk. Each mother who gave birth was assumed to have a single year of time within which to have a venous thromboembolism event (9 months during gestation and 3 months postpartum). Although the standard duration of the postpartum period is 6 weeks, we used a duration of 3 months for this analysis because we wished to include all venous thromboembolism events that could possibly be related to pregnancy. We were able to calculate age-specific woman-years for each year (for example, number of live births in Olmsted County); therefore, woman-years could be summed over the relevant time interval to calculate the correct denominator for the estimates of venous thromboembolism incidence. To calculate the incidence of venous thromboembolism during pregnancy and postpartum separately, we separated the denominator data by multiplying the total number of woman-years by 0.75 for pregnancies and by 0.25 for postpartum women. When determining incidence by trimester, half-trimester, and week, we multiplied by 0.25, 0.125, and 0.019, respectively (13 of 52 weeks, 6.5 of 52 weeks, and 1 of 52 weeks). We also calculated age-specific incidence rates for deep venous thrombosis alone and for pulmonary embolism (with or without deep venous thrombosis) among pregnant and postpartum women. Age-specific incidence rates were calculated overall (1966 to 1995) and for 3 time periods: 1966 to 1975, 1976 to 1985, and 1986 to 1995. Overall incidence rates over time were directly adjusted to the age distribution of total woman-years during the entire time period (1966 to 1995). Finally, we estimated the incidence of venous thromboembolism in Olmsted women of child-bearing years (age 15 to 45 years) that was not associated with pregnancy by subtracting pregnancy-related and postpartum-related venous thromboembolism cases from the total number of cases (numerator) and by subtracting the number of live births between 1966 and 1995 from the total person-years at risk for all Olmsted County women between the ages of 15 and 45 years (denominator). We estimated the relative risk (standardized incidence ratio) for venous thromboembolism among pregnant/postpartum Olmsted County women by dividing the observed number of venous thromboembolism events by the expected number of venous thromboembolism events determined using the incidence among nonpregnant Olmsted County women. We estimated the relative risk for venous thromboembolism during pregnancy or in the 3-month postpartum period by dividing the observed number of patients with venous thromboembolism during pregnancy or the postpartum period by the expected number with venous thromboembolism. The latter number was estimated by multiplying the age-specific incidence of venous thromboembolism attributable to other causes by the age-specific woman-years observed among the pregnant and postpartum women in Olmsted County between 1966 and 1995. We calculated exact 95% confidence intervals for all venous thromboembolism rates by assuming that the observed number of venous thromboemb

von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)†

Summary.  von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child‐bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence‐based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members

IMPORTANCE Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. OBJECTIVE To support and expand the number of health professionals able and willing to provide care for persons with SCD. EVIDENCE REVIEW Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. FINDINGS Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. CONCLUSIONS AND RELEVANCE Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

Acute Myocardial Infarction in Pregnancy. A United States Population-Based Study

Background— The purpose of this study was to determine the incidence, mortality, and risk factors for pregnancy-related acute myocardial infarction in the United States. Methods and Results— The Nationwide Inpatient Sample for the years 2000 to 2002 was queried for all pregnancy-related discharges. A total of 859 discharges included a diagnosis of acute myocardial infarction, for a rate of 6.2 (95% confidence interval [CI] 3.0 to 9.4) per 100 000 deliveries. Among these, there were 44 deaths, for a case fatality rate of 5.1%. The odds of acute myocardial infarction were 30-fold higher for women aged 40 years and older than for women <20 years of age. Single independent variables that were statistically and clinically significant, including age, race, and certain medical conditions and obstetric complications, were entered into a multivariable logistic regression model. Hypertension (odds ratio [OR] 21.7, 95% CI 6.8 to 69.1), thrombophilia (OR 25.6, 95% CI 9.2 to 71.2), diabetes mellitus (OR 3.6, 95% CI 1.5 to 8.3), smoking (OR 8.4, 95% CI 5.4 to 12.9), transfusion (OR 5.1, 95% CI 2.0 to 12.7), postpartum infection (OR 3.2, 95% CI 1.2 to 10.1), and age 30 years and older remained as significant risk factors for pregnancy-related acute myocardial infarction. Black race was eliminated as a risk factor in the multivariable analysis, which suggests that the increased incidence among black women is explained by an increased prevalence of other cardiovascular risk factors. Conclusions— Although acute myocardial infarction is a rare event in women of reproductive age, pregnancy increases the risk 3- to 4-fold. Certain medical conditions and complications of pregnancy increase the risk further and are potentially modifiable risk factors.

Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug–drug interactions and less food‐drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Am. J. Hematol. 2012.

Incidence and risk factors for stroke in pregnancy and the puerperium.

Objective: To estimate the incidence, mortality, and risk factors for pregnancy-related stroke in the United States. Methods: The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, for the years 2000–2001 was queried for International Classification of Diseases, 9th Revision, codes for stroke among all pregnancy-related discharges. Results: A total of 2,850 pregnancy-related discharges included a diagnosis of stroke for a rate of 34.2 per 100,000 deliveries. There were 117 deaths or 1.4 per 100,000 deliveries. Twenty-two percent of survivors were discharged to another facility. The risk of stroke increased with age, particularly ages 35 years and older. African-American women were at a higher risk, odds ratio (OR) 1.5 (95% confidence interval [CI] 1.2–1.9). Medical conditions that were strongly associated with stroke included migraine headache, OR 16.9 (CI 9.7–29.5), thrombophilia, OR 16.0 (CI 9.4–27.2), systemic lupus erythematosus, OR 15.2 (CI 7.4–31.2), heart disease, OR 13.2 (CI 10.2–17.0), sickle cell disease, OR 9.1 (CI 3.7–22.2), hypertension, OR 6.1(CI 4.5–8.1) and thrombocytopenia, OR 6.0 (CI 1.5–24.1). Complications of pregnancy that were significant risk factors were postpartum hemorrhage, OR 1.8 (CI 1.2–2.8), preeclampsia and gestational hypertension, OR 4.4 (CI 3.6–5.4), transfusion OR 10.3 (CI 7.1–15.1) and postpartum infection, OR 25.0 (CI 18.3–34.0). Conclusion: The incidence, mortality and disability from pregnancy related-stroke are higher than previously reported. African-American women are at an increased risk, as are women aged 35 years and older. Risk factors, not previously reported, include lupus, blood transfusion, and migraine headaches. Specific strategies, not currently employed, may be required to reduce the devastation caused by stroke during pregnancy and the puerperium. Level of Evidence: II-2

Incidence and risk factors for stroke in pregnancy and the puerperium

OBJECTIVE To estimate the incidence, mortality, and risk factors for pregnancy-related stroke in the United States. METHODS The Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, for the years 2000-2001 was queried for International Classification of Diseases, 9th Revision, codes for stroke among all pregnancy-related discharges. RESULTS A total of 2,850 pregnancy-related discharges included a diagnosis of stroke for a rate of 34.2 per 100,000 deliveries. There were 117 deaths or 1.4 per 100,000 deliveries. Twenty-two percent of survivors were discharged to another facility. The risk of stroke increased with age, particularly ages 35 years and older. African-American women were at a higher risk, odds ratio (OR) 1.5 (95% confidence interval [CI] 1.2-1.9). Medical conditions that were strongly associated with stroke included migraine headache, OR 16.9 (CI 9.7-29.5), thrombophilia, OR 16.0 (CI 9.4-27.2), systemic lupus erythematosus, OR 15.2 (CI 7.4-31.2), heart disease, OR 13.2 (CI 10.2-17.0), sickle cell disease, OR 9.1 (CI 3.7-22.2), hypertension, OR 6.1(CI 4.5-8.1) and thrombocytopenia, OR 6.0 (CI 1.5-24.1). Complications of pregnancy that were significant risk factors were postpartum hemorrhage, OR 1.8 (CI 1.2-2.8), preeclampsia and gestational hypertension, OR 4.4 (CI 3.6-5.4), transfusion OR 10.3 (CI 7.1-15.1) and postpartum infection, OR 25.0 (CI 18.3-34.0). CONCLUSION The incidence, mortality and disability from pregnancy related-stroke are higher than previously reported. African-American women are at an increased risk, as are women aged 35 years and older. Risk factors, not previously reported, include lupus, blood transfusion, and migraine headaches. Specific strategies, not currently employed, may be required to reduce the devastation caused by stroke during pregnancy and the puerperium. LEVEL OF EVIDENCE II-2.

A national study of the complications of lupus in pregnancy

OBJECTIVE This study was undertaken to determine the risk of rare complications during pregnancy for women with systemic lupus erythematosus. STUDY DESIGN By using the Nationwide Inpatient Sample from 2000-2003, we compared maternal and pregnancy complications for all pregnancy-related admissions for women with and without systemic lupus erythematosus. RESULTS Of more than 16.7 million admissions for childbirth over the 4 years, 13,555 were to women with systemic lupus erythematosus. Maternal mortality was 20-fold higher among women with systemic lupus erythematosus. The risks for thrombosis, infection, thrombocytopenia, and transfusion were each 3- to 7-fold higher for women with systemic lupus erythematosus. Lupus patients also had a higher risk for cesarean sections (odds ratio: 1.7), preterm labor (odds ratio: 2.4), and preeclampsia (odds ratio: 3.0) than other women. Women with systemic lupus erythematosus were more likely to have other medical conditions, including diabetes, hypertension, and thrombophilia, that are associated with adverse pregnancy outcomes. CONCLUSION Women with systemic lupus erythematosus are at increased risk for serious medical and pregnancy complications during pregnancy.

Liver disease in pregnancy

Severe liver disease in pregnancy is rare. Pregnancy-related liver disease is the most frequent cause of liver dysfunction in pregnancy and provides a real threat to fetal and maternal survival. A rapid diagnosis differentiating between liver disease related and unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. Research has improved our understanding of the pathogenesis of pregnancy-related liver disease, which has translated into improved maternal and fetal outcomes. Here, we provide an overview of liver diseases that occur in pregnancy, an update on the key mechanisms involved in their pathogenesis, and assessment of available treatment options.

Practice bulletin no. 123: thromboembolism in pregnancy.

Pregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5–2.0 per 1,000 pregnant women (4–9). Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries (3), or 9 % of all maternal deaths in the United States (10). In the developing world, the leading cause of maternal death is hemorrhage (11); however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death (12). The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly venous thromboembolism in pregnancy.